Lorlatinib

LORBRENA

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Pronunciation: lor-LA-ti-nib (lor-BREN-a)

Lorlatinib ballicule: receptor binding, kinetics and half-life diagram — Mechanism of action: Lorlatinib ballicule

What it isThird-generation, brain-penetrant ALK inhibitor; ALK-positive metastatic non-small-cell lung cancer.

Why this oneIt was designed for CNS penetration and covers many resistance mutations that defeat earlier ALK inhibitors.

What limits itMood change, psychosis, and cognitive slowing can require interruption or reduction; hyperlipidemia and edema need monitoring.

Lorlatinib molecular structure (skeletal formula) — Molecular structure: Lorlatinib

FDA-approved for

ALK-positive non-small cell lung cancer (2018)

FDA label

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FDA dosing	Population	Start	Target	Max
ALK-positive metastatic NSCLC	Adults	100 mg QD

Renal CLcr 15 to <30 mL/min: 75 mg QD; CLcr 30–89: no adjustment

Hepatic Severe (Child-Pugh C): 50 mg QD; mild–moderate: no adjustment

Dose reductions: 75 mg, then 50 mg; discontinue if 50 mg QD not tolerated

Instructions

Swallow whole with or without food; do not chew, crush, or split; take at the same time daily
If a dose is missed and the next is >4 hr away, take it; do not double
Discontinue strong CYP3A inducers for 3 half-lives before starting (contraindicated)
Use effective non-hormonal contraception

Available strengths

tab 25, 100 mg

Contraindications

Concomitant use with strong CYP3A inducers (risk of serious hepatotoxicity)

Cautions

Serious hepatotoxicity with strong CYP3A inducers
CNS effects (seizures, mood/cognitive/psychotic/speech changes, suicidal ideation)
Hyperlipidemia
Atrioventricular block
Interstitial lung disease / pneumonitis
Hypertension
Hyperglycemia
Embryo-fetal toxicity

Adverse reactions

Edema
Peripheral neuropathy
Weight gain
Cognitive effects
Fatigue
Dyspnea
Arthralgia
Diarrhea
Mood effects
Hypercholesterolemia
Hypertriglyceridemia
Cough

Pregnancy Can cause fetal harm (animal malformations, increased post-implantation loss, abortion)

Lactation Do not breastfeed during treatment and for 7 days after the final dose

Cost

Lorlatinib (LORBRENA)

Strength		#/mo	generic $/mo	CostPlus
25 mg	tab	30 qd		not offered
100 mg	tab	30 qd		not offered

NADAC is a voluntary CMS survey of what retail community pharmacies pay for the drugs they stock. Lorlatinib is dispensed outside retail pharmacies, so it rarely appears on surveyed invoices.

Generic entry2038 est.

NO BOXED WARNINGS

Principal riskCNS effects: mood change and cognitive slowing

Classes and tags

Clinical profile

Therapeutic safety burden3 / 4

Overdose danger2 / 4

Weight-gain liability3 / 4

Sedation liability0 / 4

QT / Torsades0 / 4

Direct muscarinic antagonism0 / 4

Embryofetal risk3 / 4

Legacy pregnancy categoryNot assigned — PLLR-era drug

Defining liabilityMyelosuppression and agent-specific hepatic, cardiac, pulmonary, neurologic or reproductive toxicity require oncology monitoring.

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